Mobilization of phagocytes from bone marrow is critical for host defense against septic infection. However, the activity of these recruited immune cells also evokes systemic inflammation leading to widespread injury in microvasculature. Tissue edema resulted from the loss of capillary integrity in vital organ systems, particularly in the lung, is detrimental. The bone marrow houses endothelial progenitor cells (EPCs) which can participate in maintaining and/or restoring microvascular homeostasis. Recent investigations have revealed that the level of circulating EPCs increases in patients with sepsis. Drop of EPC number during sepsis commonly occurs with deterioration of the disease, development of organ failure, and increase in mortality. Conversely, a greater number of circulating EPCs is associated with improved outcomes in patients with sepsis and acute lung injury. At the present time, however, little information is available about molecular signaling mechanisms underlying the regulation of marrow EPC participation in host defense. Our pilot studies on murine models of septic infection with Escherichia coli revealed that the marrow pool of EPCs bearing the lin-c-kit+Sca-1+VEGFR2+ (VEGFR2+LKS) surface marker rapidly expanded following septic infection. AP1 signaling downstream of the TLR4-JNK pathway mediated upregulation of Sca-1 expression, which played an imperative role in EPC activation. Sca-1 signals with the TLR4-ERK1/2-cyclin D1 and TLR4-ERK1/2-SP1 pathways, respectively, to promote EPC proliferation and endothelial differentiation. EPCs in the expanded marrow VEGFR2+LKS cell pool exhibited a markedly enhanced angiogenic activity. Bone marrow-derived cells actively homed to the lung and integrated in the pulmonary microvasculature following septic infection. The current project will determine the biological role of marrow EPCs in host defense against septic infection with the focus on elucidating how marrow EPCs are activated for maintaining microvascular homeostasis. Our central hypothesis is that the marrow EPC response via Sca-1 signaling is essential for maintaining microvascular homeostasis during the inflammatory response to septic infection. Three specific aims are 1) to determine if the marrow EPC response plays a pivotal role in maintaining microvascular homeostasis in vital organ tissue, typically in the lung, during host defense against septic infection, 2) to characterize Sca-1 signaling in rapid expansion of VEGFR2+LKS cell pool in the bone marrow during the inflammatory response to septic infection, and 3) to delineate Sca-1 signaling in VEGFR2+LKS cell programming for enhancing angiogenesis during the inflammatory response to septic infection. Results obtained from this investigation will greatly advance our knowledge about the role of EPC response in host defense. It will also identify key targets for developing novel therapeutic interventions to prevent and treat vital organ injury caused by the inflammatory response to septic infection.